Induction of Cell Death by Ternary Copper(II) Complexes ofl-Tyrosine and Diimines: Role of Coligands on DNA Binding and Cleavage and Anticancer Activity

2009 ◽  
Vol 48 (4) ◽  
pp. 1309-1322 ◽  
Author(s):  
Sethu Ramakrishnan ◽  
Venugopal Rajendiran ◽  
Mallayan Palaniandavar ◽  
Vaiyapuri Subbarayan Periasamy ◽  
Bangalore Suresh Srinag ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Binding ◽  
Anticancer Activity ◽  
Dna Binding And Cleavage

Molecular Mechanisms of Parthenolide-Mediated Pro-Apoptotic Activity in Acute Myeloid Leukemia Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2463-2463
Author(s):  
Mohammad Minhajuddin ◽  
Shanshan Pei ◽  
John M Ashton ◽  
Kevin Callahan ◽  
Eleni Lagadinou ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Dna Binding ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Lentiviral Vector ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Apoptotic Activity

Abstract Abstract 2463 Acute myeloid leukemia is malignant disease, characterized by an accumulation of immature myeloid cells. Recent studies have demonstrated that myeloid leukemia appears to arise from a population of leukemia stem cells (LSCs). LSCs typically reside in a quiescent state and therefore do not respond to standard chemotherapeutic agents, which generally target more actively dividing cells. However, LSCs do display certain unique molecular properties that can be exploited to target this relatively rare population of cells that drive disease pathogenesis. Specifically, NF-kB, a pro-survival transcription factor, is constitutively active in LSCs but not in normal hematopoietic stem cells (HSCs). Targeting this pathway by pharmaceutical approaches has been suggested as a potential strategy in the treatment of leukemia; however, inhibiting this pathway alone is not sufficient to strongly induce AML-specific cell death. Further investigation of pathways, that are unique to AML, is a key in designing more effective pharmacologic agents that specifically target the LSC. We have previously demonstrated that the naturally occurring compound parthenolide (PTL) induces apoptosis in primary AML cells, including the stem and progenitor cell. While the empirical anti-leukemic activity of PTL is clear, the underlying molecular mechanisms remain poorly understood. Here we investigate two properties associated with parthenolide-mediated cell death: i) activation of pro-apoptotic transcription factor p53, ii) inhibition of pro-survival transcription factor NF-kB. In order to evaluate the role of p53 signaling, AML cells were challenged with PTL resulting in the phosphorylation of p53 at serine-15, indicating activation p53 in response to PTL. To further investigate the role of p53 in PTL mediated responses, we generated a lentiviral vector expressing shRNAs specifically targeting p53. Leukemia cells were infected with the lentiviral vector encoding p53 shRNA or scramble control and evaluated by qPCR and western blot analysis. The data showed a significant knockdown of p53 mRNA and protein levels, as well as strong inhibition of p21 expression, indicating the specificity of p53 knockdown. Exposure of cells to PTL in which p53 has been specifically disrupted results in partial rescue from PTL mediated cell death, implicating the role of p53 in this response. Next, we performed a detailed analysis of the molecular mechanism by which PTL inhibits NF-kB pathway activity. Using a novel analog of PTL, we demonstrate that the compound directly binds to IKK-beta. Upon exposure to PTL, IKK-beta shows reduced kinase activity, indicating that binding of the drug directly impairs enzymatic function. Secondary to the inhibition of IKK-beta kinase activity, there is decreased phosphorylation of IkB-alpha at ser32/36, resulting in reduced proteosome mediated degradation. As expected, translocation of RelA/p65 to the nucleus was also impaired, resulting in decreased DNA binding activity as evidenced by electrophoretic mobility shift assay (EMSA). Interestingly, studies with a biotinylated analog also show that PTL appears to directly bind p65, we also observed a decreased phosphorylation of p65 at serine 536, an event mediating the transcriptional activity of DNA-bound p65. Inhibition of the NF-kB pathway by parthenolide also resulted in very significant inhibition of one of its well-known downstream target genes, ICAM-1 (CD54) at mRNA, protein and surface expression levels. Whether reduced ICAM-1 expression affects the biology of AML cells is as yet unknown. However, given the known role of ICAM-1 in integrin signaling, we propose that loss of ICAM-1 via NF-kB inhibition may impair the ability of AML cells to interact with their environment. Taken together, this study further elucidates the mechanisms by which PTL mediates pro-apoptotic activity in primary AML cells. PTL induces activation of p53 pathway and therefore knockdown of p53 by shRNA results in partial rescue from PTL mediated cell death. PTL also inhibits the NF-kB pathway, which includes binding of PTL to both IKK-beta and RelA/p65, which leads to decreased phosphorylation of IkB-alpha and reduced DNA binding of p65. In addition, we have discovered the ICAM-1 expression in AML cells is regulated by NF-kB, and that loss of NF-kB DNA binding activity results in loss of ICAM-1 expression. Disclosures: No relevant conflicts of interest to declare.

Studies on the DNA binding and anticancer activity of Ru(ii) polypyridyl complexes by using a (2-(4-(diethoxymethyl)-1H-imidazo[4,5-f][1,10] phenanthroline)) intercalative ligand

2018 ◽  
Vol 42 (2) ◽  
pp. 846-859 ◽  
Author(s):  
Ravi Kumar Vuradi ◽  
Kamakshi Dandu ◽  
Praveen Kumar Yata ◽  
Vinoda Rani M. ◽  
Rajender Reddy Mallepally ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Binding ◽  
Anticancer Activity ◽  
Graphical Representation ◽  
Polypyridyl Complexes

Graphical representation of Ru(ii) complexes causing cell death.

Interaction of rac-[M(diimine)3]2+ (M = Co, Ni) complexes with CT DNA: role of 5,6-dmp ligand on DNA binding and cleavage and cytotoxicity

2011 ◽  
Vol 40 (13) ◽  
pp. 3245 ◽  
Author(s):  
Sethu Ramakrishnan ◽  
Eringadothi Suresh ◽  
Anvarbatcha Riyasdeen ◽  
Mohamad Abdulkadhar Akbarsha ◽  
Mallayan Palaniandavar
Keyword(s):  
Dna Binding ◽  
Ct Dna ◽  
Dna Binding And Cleavage

scholarly journals Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity

2013 ◽  
Vol 371 (1995) ◽  
pp. 20120135 ◽  
Author(s):  
Alycia M. Palmer ◽  
Bruno Peña ◽  
R. Bryan Sears ◽  
Olivia Chen ◽  
Maya El Ojaimi ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Charge Transfer ◽  
Dna Binding ◽  
Coordination Sphere ◽  
Ligand Exchange ◽  
Ligand Substitution ◽  
Tissue Penetration ◽  
Ligand Charge Transfer

The cyclometallated Ru(II) complexes cis -[Ru(phpy)(phen)(CH 3 CN) 2 ](PF 6 ) ( 1 ; phpy − =deprotonated 2-phenylpyridine, phen=1,10-phenanthroline) and cis -[Ru(phpy)(bpy)(CH 3 CN) 2 ](PF 6 ) ( 2 ; bpy=2,2′-bipyridine) were investigated as potential agents for photodynamic therapy. The presence of phpy − in the coordination sphere results in a red-shift of the Ru→phen and Ru→bpy metal-to-ligand charge transfer of 1 and 2 , respectively, thus improving the tissue penetration of light while maintaining the efficient photo-induced ligand exchange required for DNA binding. The 14-fold enhancement of OVCAR-5 cell death that occurs upon irradiation with 690 nm light can be attributed to photo-aquation. The role of glutathione (GSH) on the toxicity of the complex was also explored. Complexes 1 and 2 undergo ligand substitution in the presence of GSH in the dark, such that the metal may covalently bind to biomolecules. The combination of photo-induced ligand exchange and GSH-facilitated ligand exchange may explain the observed cytotoxicity.

Synthesis, characterization, DNA binding and cleavage, BSA interaction and anticancer activity of dinuclear zinc complexes

2012 ◽  
Vol 41 (39) ◽  
pp. 12220 ◽  
Author(s):  
Chun-Yan Gao ◽  
Xin Qiao ◽  
Zhong-Ying Ma ◽  
Zhi-Gang Wang ◽  
Jing Lu ◽  
...  
Keyword(s):  
Dna Binding ◽  
Anticancer Activity ◽  
Zinc Complexes ◽  
Dna Binding And Cleavage ◽  
Bsa Interaction

Copper(II) complexes of tridentate pyridylmethylethylenediamines: Role of ligand steric hindrance on DNA binding and cleavage

2005 ◽  
Vol 99 (8) ◽  
pp. 1717-1732 ◽  
Author(s):  
Angamuthu Raja ◽  
Venugopal Rajendiran ◽  
Palanisamy Uma Maheswari ◽  
Ramalingam Balamurugan ◽  
Colin A. Kilner ◽  
...  
Keyword(s):  
Dna Binding ◽  
Steric Hindrance ◽  
Dna Binding And Cleavage
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